ABSTRACT Colorectal cancer (CRC) screening and appropriate follow-up can reduce incidence and mortality. The US Preventive Services Task Force (USPSTF) recommends CRC screening through a variety of invasive and non- invasive tests for individuals aged 50 to 75 years. Evidence-based interventions (EBIs) and other strategies exist to promote CRC screening, but adoption and implementation of these are limited, especially in CHCs. Our hypothesis is that a Hub and Spoke multilevel intervention will be superior to usual care. The hub will be Health Quality Partners of Southern California (HQP), a non-profit organization comprised of 16 CHC systems (spokes), serving 135 rural and urban clinic sites. We propose a 2-phase study to pilot and optimize (Phase I) and rigorously test (Phase II) the Hub and Spoke approach and its impact on CRC screening, follow-up, and usual care. UG3 Planning/Exploratory Phase AIM: Pilot test the feasibility, acceptability, and preliminary outcomes of a multilevel intervention for CRC screening, follow-up, and referral-to-care using a mixed methods approach. The intervention includes HQP hub-based delivery of centralized mailed FIT to patients served by individual CHCs-spokes plus complimentary provider and clinic-level interventions at CHCs, and coordination of a standardized navigation strategy delivered by CHCs for abnormal FIT follow-up. UH3 Implementation Phase. We will conduct a 2-arm pragmatic randomized trial to assess impact of a regionally-developed multilevel intervention to increase CRC screening, follow-up, and referral-to-care among CHC patients. The trial will be guided by the Pragmatic, Robust Implementation and Sustainability Model (PRISM), which includes outcomes from the Reach, Effectiveness, Adoption, Implementation, Maintenance (RE-AIM) framework and expands them with contextual constructs. Aim 1. Assess effectiveness of the multilevel intervention based on: 1) improvement in proportion up-to-date with screening 3 years post implementation; 2) proportion with abnormal FIT who complete diagnostic colonoscopy within 6 months; and 3) proportion with CRC completing first treatment evaluation. Aim 2. Evaluate the implementation, scalability, and sustainability of a multilevel implementation strategy. Implementation will be evaluated with a mixed methods approach using the RE-AIM outcomes of Reach, Adoption, and Implementation as well as the PRISM constructs of Intervention Characteristics and Recipients from perspective of multiple stakeholders (i.e. patients, front-line staff, and operational leaders). We will also calculate replication costs. Scalability and Sustainability will be evaluated using the RE-AIM outcome of Maintenance and the PRISM constructs of Implementation & Sustainability Infrastructure and External Environment. Our study will help accelerate progress in CRC prevention in underserved populations by identifying multilevel intervention strategies that are scalable to additional CHCs in the region, with potential for larger scale implementation.